Treating Mood and Anxiety Disorders in Children & Adolescents

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1 Treating Mood and Anxiety Disorders in Children & Adolescents Daniel S. Pine, MD Section on Development & Affective Neuroscience Disclosures: Conflicts Sources of Research Support National Institute of Mental Health Paid Editorial Relationship Am J Psychiatry Deputy Editor Consulting Relationships None Role in pharmacology, DSM-5, RDoC FDA Committee & Black Box Vote Off-Label use Stock Equity (>$10,000) None Speaker s Bureau None My perspective Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Current Treatments Finding Novel Treatments Underlying neurobiology Using neuroscience to guide discovery? Daniel S. Pine, MD 1

2 Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications The Diagnostic and Statistical Manual DSM-III DSM-5 Classification & Anxiety Mostly minor change, except for structure revision process placement of child disorders broad disorder groupings move toward dimensions Changes in anxiety minor (e.g., vs. Autism) Daniel S. Pine, MD 2

3 DSM-5 & Anxiety OCD Associations with tics, ADHD Basal ganglia dysfunction, PANDAS PTSD Leckman, Leonard, Peterson, Rosenberg, Swedo, others Longitudinal associations with wide array of disorders HPA axis dysfunction DeBellis, Heim, Nemeroff, Pynoos, others Social Anxiety, GAD, Separation Anxiety, [Phobias] Considered as a group in most major treatment studies Biederman, Kendal, Kessler, Pine, Rosenbaum, Weissman, others Specific Association with MDD and distress vs. fear? Particularly GAD? DSM-5 Classification & Mood Disorders Mostly minor, except bipolar disorder Controversy about bipolar disorder Classic presentation is rare How to classify chronically irritable child? Disruptive Mood Dysregulation Disorder RDoC Based in neuroscience Focuses on Narrow Behaviors Focuses on Dimensions Daniel S. Pine, MD 3

4 Longitudinal Data Clinic-based Family-based Community-based Sub-clinical Precursors Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder Disorder as Adolescents? Disorder as Adults? No Yes No Yes Pine et al. 1998, 2001, 2002 Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder Disorder as Adolescents? Disorder as Adults? No Yes No Yes Pine et al. 1998, 2001, 2002 Daniel S. Pine, MD 4

5 Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder Disorder as Adolescents? Disorder as Adults? No Yes No Yes Pine et al. 1998, 2001, 2002 Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder Disorder as Adolescents? Disorder as Adults? No Yes No Yes Pine et al. 1998, 2001, 2002 Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Daniel S. Pine, MD 5

6 Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Current Treatments Treatment Major Depression SSRI Medications Psychotherapy: CBT? & IPT? Anxiety Disorders SSRI Medications Psychotherapy: CBT SSRIs, CBT, & Efficacy in Pediatric Anxiety Daniel S. Pine, MD 6

7 SSRIs, CBT & Pediatric Anxiety: Efficacy SSRI evidence for efficacy in GAD, social anxiety, separation anxiety disorder Particularly good evidence for fluvoxamine, fluoxetine, paroxetine, sertraline, (duloxetine, venlafaxine) Also good evidence for CBT Comparative efficacy of SSRIs & CBT? Rates of Improvement Meta-Analysis: Rates of Improvement Study Difference PBO SSRI RUPP Anxiety Study (2001) 47% 29% 76% Birmaher et al. (2003) 25% 36% 61% Rynn et al. (2001) 80% 10% 90% Wagner et al. (2004) 40% 38% 78% Walkup et al. (2008) 31% 24% 55% Rynn et al. (2007) 12% 24% 36% Total 30% 31% 61% NNT=3.3 Daniel S. Pine, MD 7

8 Cognitive Behavioral Therapy Evidence of Efficacy Quite strong Specificity in therapy procedures How does CBT work? Make fear hierarchy Learn new techniques Graded exposure Importance of patient s control and success Role of the therapist? Daniel S. Pine, MD 8

9 SSRIs, CBT, & Efficacy in Pediatric Major Depressive Disorder (MDD) SSRIs and Pediatric MDD: Efficacy fluoxetine works (3 of 3½ studies) Weak evidence for sertraline (not really), citalopram (2 of 4 studies) FDA Approval: fluoxetine/prozac; escitalopram/lexapro Some (very weak) evidence for paroxetine Virtually no evidence for other agents What gives? Data in adults that strong? Differences among the SSRIs? Differences in placebo response, sample, assessment Results Fluoxetine vs. placebo CBT vs. placebo What does this mean? Strong role of expectancy What do we recommend to patients? First Line Treatments? Daniel S. Pine, MD 9

10 Bottom Line? Only significant benefit was for CBT SSRIs and Controversy SSRIs and Controversy Biased reporting of data for efficacy Daniel S. Pine, MD 10

11 Biased Reporting in Adult Antidepressant Trials Turner et al. NEJM 2008 Bias in Publication Bias in Magnitude of Clinical Effect SSRIs and Controversy Concerns about suicidal ideation Antidepressants and Thoughts About Suicide FDA Analysis from December, 2006 Daniel S. Pine, MD 11

12 SSRIs and Controversy FDA & Black Box Bottom Line of the SSRIs SSRIs are very effective in the treatment of pediatric anxiety (and OCD). Of the SSRIs, only fluoxetine and citalopram have been shown to be effective in pediatric MDD, and the NNT is large. Increased risk of suicidality with SSRIs is real, but the magnitude of the effect is small. Pediatric Bipolar Disorder Daniel S. Pine, MD 12

13 DSM-5 Classification & Mood Disorders Mostly minor, except bipolar disorder Controversy about bipolar disorder Classic presentation is rare How to classify chronically irritable child? Disruptive Mood Dysregulation Disorder Treatment of Bipolar Disorder Wide use of many medications FDA: (age 10 to 17) aripipazole (Abilify) quetiapine (Seroquel) risperidone (Risperdol) olanzapine (Zyprexa) (ages 13 to 17) No evidence for anticonvulsants FDA Approval for lithium (13 to 17) Not much other strong data; concerns about safety Daniel S. Pine, MD 13

14 Practical Points Anxiety easier to treat than mood Two good treatments available Importance of exposure in anxiety Mood disorders are very serious; handle with care and experts Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Current Treatments Finding Novel Treatments Underlying neurobiology Using neuroscience to guide discovery? SEROTONIN ANATOMY Daniel S. Pine, MD 14

15 SEROTONIN ANATOMY Development, Anxiety, & 5-HT1a R Gross et al. Nature 2002 The effect of SSRIs on developing nervous system is not fully understood Ansorge et al (2004) Science 5-HT1a receptor must be present pre-adolescence to rescue anxious phenotype. Daniel S. Pine, MD 15

16 VISUAL CORTEX VISUAL THALAMUS AMYGDALA HEART RATE BLOOD PRESSURE MUSCLE LeDoux. Sci Am. 1994;270:50. Attention Retraining Therapy Changes in SPAI in n=36 patients with Social Phobia Schmidt et al Training of Attention Meta-Analysis: Training Studies Hakamata et al Daniel S. Pine, MD 16

17 Randomized Controlled Trial Four-Week Treatment Outcomes in Pediatric Anxiety Disorders Eldar et al Altered Response to Stress Training of n=15 Attention n=15 n=10 Eldara, Ricona, & Bar-Haim 2008 Daniel S. Pine, MD 17

18 Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder Disorder as Adolescents? Disorder as Adults? No Yes No Yes Pine et al. 1998, 2001, 2002 Ressler & Davis 2003 Ressler & Davis 2003 Extinction: Not forgetting but new learning Anxiety disorders as problems in new learning Ressler & Davis 2003 Ressler & Davis 2003 Daniel S. Pine, MD 18

19 NMDA manipulation NMDA manipulations? Ressler & Davis 2003 Ressler & Davis 2003 Acrophobia within the virtual environment is improved with D-cycloserine Data on Social Phobia are equivocal Hoffman et al. Am J Psychiatry 2013;170: Ressler, K. J. et al. Arch Gen Psychiatry 2004;61: Panic Disorder is improved with D-cycloserine Positive findings in some Guastella et al. 2008; Hofmann et al. 2006; Wilhelm et al. 2008; but not in other studies. Guastella et al. 2007; Kushner et al. 2007; Rothbaum et al. 2014; Storch et al. 2007, 2010 Copyright restrictions may apply. Otto et al. Biol Psychiatry 2010 Practical Points We know much about anxiety Basic knowledge informs treatment Informs treatments we have May lead to new treatments Daniel S. Pine, MD 19

20 Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Current Treatments Finding Novel Treatments Underlying neurobiology Using neuroscience to guide discovery? Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Current Treatments Finding Novel Treatments Underlying neurobiology Using neuroscience to guide discovery? Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Current Treatments Finding Novel Treatments Underlying neurobiology Using neuroscience to guide discovery? Daniel S. Pine, MD 20

21 Outline & Objectives Classifying Pediatric Mood & Anxiety Broad categorization schemes Outcome & treatment implications Current Treatments Finding Novel Treatments Underlying neurobiology Using neuroscience to guide discovery? Daniel S. Pine, MD 21

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